Addition of an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy improves survival in advanced malignancies

Abstract

Studies have shown that cancer requires two conditions for tumor progression: cancer cell proliferation and an environment permissive to and conditioned by malignancy. Chemotherapy aims to control the number and proliferation of cancer cells, but it does not effectively control the two best-known conditions of the tumor-permissive environment: neoangiogenesis and tolerogenic immunity. Many malignant diseases exhibit poor outcomes after treatment with chemotherapy. Therefore, we investigated the potential benefits of adding an induction regimen of antiangiogenesis and antitumor immunity to chemotherapy in poor outcome disease. In a prospective, randomized trial, we included patients with advanced, unresectable pancreatic adenocarcinomas, non-small cell lung cancer, or prostate cancer. Two groups of each primary condition were compared: group 1 (G1), n = 30, was treated with the standard chemotherapy and used as a control, and group 2 (G2), n = 30, was treated with chemotherapy plus an induction regimen of antiangiogenesis and antitumor immunity. This induction regimen included a low dose of metronomic cyclophosphamide, a high dose of Cox-2 inhibitor, granulocyte colony-stimulating factor, a sulfhydryl (SH) donor, and a hemoderivative that contained autologous tumor antigens released from patient tumors into the blood. After treatment, the G2 group demonstrated significantly longer survival, lower blood level of neoangiogenesis and immune-tolerance mediators, and higher blood levels of antiangiogenesis and antitumor immunity mediators compared with the G1 group. Toxicity and quality of life were not significantly different between the groups. In conclusion, in several advanced malignancies of different primary localizations, an increase in survival was observed by adding an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy.

Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy

“…In a prospective, randomized trial, patients with advanced, unresectable pancreatic adenocarcinoma, non-small cell lung cancer, or prostate cancer were given either standard chemotherapy (control group) or were additionally given low-dose metronomic cyclophosphamide (50 mg/day, orally) combined with G-CSF, a sulfhydryl donor, a Cox2 inhibitor, and a preparation of autologous tumor antigens (experimental group). The experimental group displayed higher anti-tumor immunity after three months and a significantly longer mean survival time [93]. In another study, 28 progressive metastatic melanoma patients were treated with low-dose metronomic cyclophosphamide (50 mg/twice daily, orally; 1 week on, and 1 week off) together with celecoxib (200 mg daily), followed by vaccination with DCs [94].…”

Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors

“…In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, an injection of a low dose (50 mg/kg) of cyclophosphamide ensured the optimal survival of adoptively infused CD8 T cells, while the highest dose (200-400 mg/kg) was highly toxic and induced lymphopenia [149]. Consistent with preclinical data, low doses of cyclophosphamide triggered anti-tumor T cell responses and Treg depletion in advanced human cancers [150][151][152]. Ideally, the dose of chemotherapy should be high enough to ensure the induction of ICD but remain under the threshold inducing severe lymphopenia and immunosuppression.…”

Clinical benefit of COX-2 inhibitors in the adjuvant chemotherapy of advanced non-small cell lung cancer: A systematic review and meta-analysis

“…The median survival time is 6-10 mo for patients who are diagnosed with advanced NSCLC in performance status 0-2 while adopting palliative first-line chemotherapy[ 3 - 5 ]. For decades, chemotherapy has been the cornerstone of standard cancer treatment[ 6 ]. At present, the efficacy of various chemotherapy regimens has reached its peak[ 7 ].…”